The etiology and pathogenesis of schizophrenia, autism and the major mood disorders is still unclear. Genetic factors certainly play an important role in the development and pathogenesis of these disorders. However, environmental factors contribute, and a combination of the two most probably operates, as is often seen.
A typical example of such a combined genetic and dietary based disease is Føllings disease, in which a genetic defect in the metabolism of phenylalanine results in severe maldevelopment of the brain. Dietary reduction of phenylalanine intake, however, prevents the disease development provided it is started shortly after birth. Therefore, an intensive search for environmental factors is going on, the discovery of which could strongly improve therapy of these devastating diseases. Such environmental factors could be infectious or dietary, or even both.
About 20 ago F. C. Dohan (Dohan, F. C (1983), More on celiac disease as a model for schizophrenia, Biological psychiatry, 18; 561-564; and Dohan, F. C (1988), Genetic hypothesis of idiopathic schizophrenia: its exorphin connection, Schizophrenia Bull, 14:489-494) discussed a possible relation between celiac disease and schizophrenia. Celiac disease is an inflammatory bowel disorder due to intolerance to peptides derived from gluten proteins. This condition is occasionally accompanied by psychiatric and neurological symptoms. A relation between celiac diseases and psychiatric and neurological disease is further supported by several recent investigations (KnivsBerg, Ann-Mari, Wiig, Kirsti, Lind, G. Nødland, M., Reichelt, K. L (1990), Dietary Intervention in Autistic Syndromes Brain Dysfunct, 3, 315-327; KnivsBerg, A. M. Reichelt, K. L, G. Nødland, M., Høyen, T (1990), Autistic Syndromes and Diet: a follow-up study, Scandinavian Journal of Educational Research; 39, 223-236; Whitley, P., Rodgers, J., Savery, D. and Shattock, p. (1999), An gluten-free diet as an intervention for autism and associated disorders: perliminary findings., Autism; 3: 45-65; Hadjivassilou, M., Grunewald, R. A, Chattopadhyay, A. K et al (1998), Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. The Lancet: 352, 1582-1586).
In 1979, Panksepp (Panksepp, J. A neurochemical theory of autism Trends in Neuroscience 1979; 2: 174-177) proposed the opioid excess theory in which he suggested that disturbance of endogenous opioid is part of the pathogenesis in autism. At the same time K. L. Reichelt et al (Hole, K., Bergslien, A. A, Jørgensen, H. et al (1979) A peptide containing fraction in the urine of schizophrenic patients which stimulates opiate receptors and inhibits dopamine uptake. Neuroscience; 4:1883-1893) isolated biologically active peptides from the urine from schizophrenic patients. Drysdale (Drysdale, A. Deacon, R., Lewis, R. et al (1982) A peptide containing fraction of plasma of schizophrenic patients which binds to opiate receptors and induces hyperactivity in rats Neuroscience; 7: 1567-1574) found a peptide-containing fraction in plasma from schizophrenic patients that were found to bind to opiate receptors, which induced hyperactivity in rats. Both groups showed that the principles they isolated had opioid and dopaminergic activity. At the present time, the best-characterized peptides found to be elevated in psychiatric patients, are exorphins derived from gluten and bovine caseins.
Several studies show elevated peptide levels in the urine of autistic persons (Reichelt, K. L and Teigland-Gjerstad, B (1995) Decreased urinary peptide excretion in schizophrenic patients after neuroleptic treatment sychiatry Research, 58; 171-176; Shattock, P. and Savery, D. (1997) Evaluation of Urinary Profiles obtained from people with autism and associated disorderes. Part 1:Classification of subgroups http://osiris.ac.uk/autism/ps97.htm) The inventors of the present invention have confirmed the urinary peptide pattern in normal and autistic individuals, and found higher levels in the autistic children.
Gluten Derived Exorphins
During the last year it has become clear that exorphins, a class of biologically active short peptides are produced enzymatically from gluten proteins in the gut during digestion. (Fukodome et al 1993, 1996, Froetshel 1996). These peptides, which are 4-5 amino acids long, have opioid activity and are relatively specific for δ-receptors.
Some representative gluten exorphins have the following amino acid sequence:                Exorphin A5: Gly-Tyr-Tyr-Pro-Thr (SEQ. ID. No. 1)        Exorphin A4: Gly-Tyr-Tyr-Pro (SEQ. ID. No. 2)        Exorphin B5: Tyr-Gly-Gly-Trp-Leu (SEQ. ID. No. 3)        Exorphin B4: Tyr-Gly-Gly-Trp (SEQ. ID. No. 4)        Exorphin C: Tyr-Pro-Ile-Ser-Leu (SEQ. ID. No. 5)        
DeSantis et al (1997) (DeSantis, A. et al (1997) Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet, Journal of internal medicine 242:421-423) has shown regression of schizophrenic symptoms and SPECT (Single Photon Computer Tomography) abnormalities in a celiac patient after a gluten-free diet. An involvement of gluten peptides in neurological diseases has recently been shown in celiac ataxia further supporting neuropathological effects of such substances (Hadjuvassilou et al 1998) (Hadjivassilou, M., Grunewald, R. A, Chattopadhyay, A. K et al (1998) Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. The Lancet:352, 1582-1586).
Furthermore, Wakefield 1998 (Wakefield, A. J., Murch, S H, Anthony, A. (1998) Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children The Lancet 351: 637-641 and 2000) (Wakefield, A. J. Anthony A, Murch S H. (2000) Enterocolitis in Children With Developmental Disorders The American Journal of Gastroenerology 95: 2285-2295) has recently found a relation between ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in a group of children. Reichelt et al, 1998, (Reichelt, W. H, Ek, J. Stensrud, M and Reichelt, K. L Peptide excretion in celiac disease. Journal of Pediatric gastroenterology and Nutrition, 1998; 26: 305-309) have demonstrated increased peptide excretion in celiac disease. Accordingly, the findings of gluten derived exorphins in the urine of patients with schizophrenia; autism and mood disorders strongly suggest a causal relation, further supported by dietary experiments.
The present invention is based on these findings, i.e. that some specific peptides are found at concentrations above normal, and that this is correlated to various disorders or symptoms. In order to prevent or treat such diseases it is thus anticipated that compositions capable of lowering this elevated peptide concentration should have an effect on the disease state.
Casomorphins
During the last decade it has also been demonstrated that peptide sequences derived from incomplete catabolism of milk proteins have opioid activity (Teschemacher, H., Koch, G., and Brantl, V. (1997) Milk Protein-Derived Opoid Receptor Ligands Biopol. 43: 99-117). Caseins degrade to peptides with 3-20 amino acids, some of which have opioid activity and are termed casomorphins.
Representative examples of the amino acid sequence of some casomorphins:
β-casomorphin 1-8: Tyr-Pro-Phe-Pro-Gly-Pro-Ile-Pro (SEQ. ID. No. 6);
β-casomorphin 1-7: Tyr-Pro-Phe-Pro-Gly-Pro-Ile (SEQ. ID. No. 7);
β-casomorphin 1-5: Tyr-Pro-Phe-Pro-Gly (SEQ. ID. No. 8);
β-casomorphin 1-4: Tyr-Pro-Phe-Pro (SEQ. ID. No. 9);
β-casomorphin 1-4 amide: Tyr-Pro-Phe-Pro-NH2 (SEQ. ID. No. 9).
Recently, Sun et al (1999) (Sun, Z., Cade, J. R, Fregly, M. J. and Privette, R. M. (1999) β-casomorphin induces Fos-like immunoreactivity in discrete brain regions relevant to schizophrenia and autism., Autism; 3: 67-83) showed that β-casomorphin 1-7, which is one of the peptides isolated from the urine from patients with schizophrenia and autism that cause behavioral changes in rats. This peptide also induces Fos-like immunoreactivity in discrete brain regions relevant to schizophrenia and autism (Sun et al 1999).
Intact peptides can be absorbed from the small bowel. In humans it was demonstrated that bovine casein releases peptides that can pass to the blood during digestion of milk or yogurt (Chabance et al, 1998) (Chabance, B. Et al (1998) Casein peptide release and passage to the blood in humans during digestion of milk or yogurt, Biochimie, 80:155-165). In normal individuals, however, it appears that the peptidases in the gut and in the blood degrades such peptides rapidly (Teschemacher, H., Koch, G., and Brantl, V. (1997) Milk Protein-Derived Opoid Receptor Ligands Biopol. 43: 99-117). However, this seem not to be the case for patients suffering of the medical conditions described above, where it is believed that such an insufficient degradation or catabolism of these specific food derived peptides contribute to the development and severity of such diseases.
Clinical improvement in autistic children has been demonstrated in clinical trials following exclusion of either gluten or milk and milk products form the diet. (Reichelt, et al, 1990, Lucarelli 1995, Knivsberg et al, 1997, Whitley et al, 1999). In addition several causistic reports support the effect of gluten free and casein free diets in these patients.
Further, Singh and Kay reported in 1976 that wheat gluten could be a pathogenic factor in schizophrenia, and Reichelt et al (1990) have shown that a gluten-free diet effects the urinary peptide secretion and clinical state in schizophrenic patients.
Hyperpeptiduria, i.e. increased concentration of peptides in the urine, is regularly found in autism, schizophrenia and major depressive disorders (Reichelt, W. H, Knivsberg, A. M., Nødland, M., Stensrud, M. and Reichelt, K. L. (1997), Urinary peptide level and patterns in autistic children from seven countries, and the effect of dietary intervention after 4 years., Dev. Brain Dysfunct; 10: 44-55; Whitley, P., Rodgers, J., Savery, D. and Shattock, p. (1999), An gluten-free diet as an intervention for autism and associated disorders: perliminary findings. Autism; 3: 45-65; Reichelt, K. L., Sagedal, E, Landmark, J., Sangvik, B. T., Eggen, O., and Scott, H. (1990), The effect of gluten-free diet on urinary peptide secretion and clinical state in schizophrenia., Journal of Orthomolecular medicine, 5: 223; Reichelt, K. L., Ekrem, J. and Scott, H. (1990), Gluten, milk proteins and autism: dietary intervention effects on behavior and peptide secretion., Journal of applied nutrition; 42: 1-11; Sun, Z. And Cade, J. R (1999), A peptide found in schizophrenia and autism cause behavioral changes in rats. Autism; 3: 85-95; Wakefield, A. J. et al. (1998), Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children, The Lancet 351: 637-641; Reichelt, K. L and Stensrud, M (1998) Increase in urinary peptides prior to the diagnosis of schizophrenia, Schizophrenia Research; 1998; 34: 211-213). The peptide pattern varies considerably between patients, which may be due to the presence of dietary peptides without biological effect, and not related to enzyme defects in the psychiatric diseases. However, even peptides without biological activity may act as peptidase inhibitors. During dietary treatment and after use of neuroleptic agents, urinary peptide patterns are normalized. Other gut-derived substances may also be involved, as Shattock has found that indoly-acryloylglycin (IAG) is present in the urine of autistic children, and Friedman discloses the presence of the nonhuman peptide dermorphin.
These findings indicate that there is a correlation between a concentration above normal for some specific peptides and the development of certain diseases, especially neurological disorders. Further, it is clearly established that some of these “pathogenic peptides” are derived from food proteins, e.g. caseins and gluten.
Further, there is evidence for genetic alterations in plasma dipeptidyl peptidase IV enzyme activity in depression and schizophrenia (Maes et al, 1994, 1996) (Maes, M., Goossens, F., Scharpe, S. et al (1994) Lower serum prolyl endopeptidase enzyme acivity in major depression: Further evidence that peptidases play allmenn role in the pathophysiology of depression. Biol. Psychiat.; 35: 545-552 Maes, M., Goossens, F., Scharpe, S. et al (1994) Lower serum prolyl endopeptidase enzyme acivity in major depression: Further evidence that peptidases play allmenn role in the pathophysiology of depression. Biol. Psychiat.; 35: 545-552), which may also affect intestinal enzyme activity. Defective metabolism of gut-derived peptides is reflected in the excretion pattern of such substances.
In conclusion, these investigations strongly support the idea that symptoms in such psychiatric disorders as schizophrenia, ADHD, autism and depressions, at least partly, result from incomplete breakdown and/or increased uptake of gut-derived peptides.